Pyrrole compounds

ABSTRACT

Compounds of formula (I): ##STR1## wherein: R represents hydrogen, alkyl, optionally-substituted amino, or linear or branched (C 1  -C 6 )-acyl, 
     R 1  and R 2 , which may be identical or different, each represents independently of the other aryl, heteroaryl, or (C 5  -C 7 )-cycloalkyl, or one of those groups optionally substituted, 
     A, together with the atoms in common with the pyrrole, represents saturated or unsaturated, monocyclic or bicyclic (C 3  -C 12 )-cycloalkyl, or a saturated heterocycle having 5 to 7 ring members and containing one or two nitrogen, or 7-oxabicyclo[2.2.1]heptane, or one of those groups optionally substituted, 
     their isomers, and also addition salts thereof with a pharmaceutically-acceptable acid or base, pharmaceutical compositions thereof, and use thereof as medicaments.

FIELD OF THE INVENTION

The present invention relates to new pyrrole compounds.

A number of pyrrole compounds having a dihydro- or tetrahydro-isoindolestructure are described in the literature. Of those, attention may bedrawn to compounds containing in the 1 and 3 positions a phenyl group(Bull. Chem. Soc. Jp., 1993, 66 (9), 2707-2713), a substituted phenylgroup (Chem. Ber., 1972, 105, 1258-1278), or a phenyl group and anisoquinoline (J. Org. Chem., 1981, 46, 1656 ; Bull. Soc. Chem. Belges,1992, 101 (2), 109-112). Those particular compounds are disclosed inthose documents through their method of synthesis or their spectralcharacteristics. No therapeutic activity is known or disclosed for thosecompounds.

The novelty of the compounds of the invention, in addition to the factthat they are new, lies in their selective inhibitory activity inrelation to cyclooxygenase-2 (COX 2) and of inducible nitric oxydesynthase (iNOS)

The prostaglandins (PG) play an important role in the development ofinflammatory reactions. Since the discovery by Vane in 1971 (Nature,1971, 321, 232-235), who made an association between the activity ofnon-steroidal anti-inflammatories (NSAIs) and inhibition of thecyclooxygenase pathway of the arachidonic cascade, inhibition of theproduction of PGs constitutes the main target in the discovery ofcompounds having an anti-inflammatory activity.

However, compounds active against the pain and inflammation induced byPGs are also inhibitors of physiological processes that are regulated byPGs independently of the inflammatory reaction, and hence produceundesirable side effects such as gastric ulcers and/or effects on thekidneys.

The discovery of an isoenzyme of cyclooxygenase (COX) in 1991 (J. Biol.Chem., 1991, 266, 12866-12872 Proc. Natl. Acad. Sci. USA, 1991, 88,2692-2696) made it possible to establish the difference betweenconstitutive COX (COX 1), which is widely distributed in the organism,especially in the stomach and the kidneys, and inducible COX (COX 2),the synthesis of which is induced by inflammatory and mitogenic stimuli.The hypothesis has thus been put forward that a selective inhibitor ofCOX 2 might be a powerful anti-inflammatory compound withoutgastrointestinal and/or renal side-effects.

Interleukin 1β (IL1β) is produced by macrophages and is the dominantfactor of a large number of inflammatory processes. In particular, IL1βstimulates the cells that synthesise and express COX 2, yielding PGs.IL1β is also responsible for the expression and synthesis of inducibleNO synthase and of the proteases that are involved in the degradation ofthe extracellular matrix of cartilage.

The inflammatory processes mediated by the COXs are common to a largenumber of pathologies. They play an important role in rheumatology andespecially in rheumatoid arthritis and arthrosis. The inhibition of COX2 has been proposed for limiting the inflammatory reactions occurring inthe development of those pathologies. The inhibition of IL1β alsoconstitutes a target that allows regulation of, on the one hand, theinflammation and, on the other hand, the articular degradationcharacteristic of those pathologies.

In addition to the fact that the compounds of the present invention arenew, they have proved to be specific inhibitors of COX 2, IL1β and iNOS,making them potentially useful in the treatment of the inflammatoryprocesses that occur especially in rheumatic disorders, such asarthrosis and rheumatoid arthritis, but also in atherosclerosis, cancer,etc.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates more especially to the compounds offormula (I) ##STR2## wherein R represents:

a hydrogen atom,

a linear or branched (C₁ -C₆)-alkyl group optionally substituted by oneor more, identical or differents groups selected from hydroxy, linear orbranched (C₁ -C₆)-alkoxy, carboxy and linear or branched (C₁-C₆)-alkoxycarbonyl groups,

an amino group optionally substituted by one or two identical ordifferent groups selected from linear or branched (C₁ -C₆)-alkyl, linearor branched (C₁ -C₆)-alkoxycarbonyl, linear or branched aryl-(C₁-C₆)-alkoxycarbonyl, linear or branched (C₁ -C₆)-alkylsulphonyl andarylsulphonyl,

or a linear or branched (C₁ -C₆)-acyl group,

R₁ and R₂, which may be identical or different, each representsindependently of the other an aryl, heteroaryl or (C₃ -C₇)-cycloalkylgroup, it being possible for each of those groups optionally to besubstituted by one or more identical or different groups selected from:

halogen,

linear or branched (C₁ -C₆)-alkyl optionally substituted by one or morehalogen atoms, hydroxy groups, linear or branched (C₁ -C₆)-alkoxygroups, amino groups or linear or branched (C₁ -C₆)-alkoxycarbonylgroups,

linear or branched (C₁ -C₆)-alkoxy optionally substituted by an aminogroup that is itself optionally substituted by one or two identical ordifferent linear or branched (C₁ -C₆)-alkyl groups,

linear or branched (C₁ -C₆)-trihaloalkoxy,

linear or branched (C₁ -C₆)-acyl,

hydroxy, nitro, cyano, mercapto, carboxy,

amino optionally substituted by one or two identical or different groupsselected from linear or branched (C₁ -C₆)-alkyl, linear or branched (C₁-C₆)-alkylcarbonyl and linear or branched (C₁ -C₆)-alkylsulphonyl,

linear or branched (C₁ -C₆)-alkoxycarbonyl,

linear or branched (C₁ -C₆)-alkylthio,

sulphonyl substituted by a linear or branched (C₁ -C₆)-alkyl group or anamino group itself optionally substituted by one or two identical ordifferent linear or branched (C₁ -C₆)-alkyl groups, and

a saturated or unsaturated, monocyclic or bicyclic heterocycle havingfrom 5 to 10 ring members and containing 1, 2 or 3 identical ordifferent hetero atoms selected from nitrogen, oxygen and sulphur,optionally substituted by one or more identical or different groupsselected from halogen, linear or branched (C₁ -C₆)-alkyl and linear orbranched (C₁ -C₆)-alkoxy,

A represents, together with the atoms in common with the pyrrole:

a saturated or unsaturated, monocyclic or bicyclic (C₃ -C₁₂)-cycloalkylgroup (with the proviso that the unsaturation(s) present in thecycloalkyl does(do) not confer on it an aromatic character),

a saturated heterocycle having from 5 to 7 ring members and containingone or two nitrogen atoms,

or a 7-oxabicyclo[2.2.1]heptane radical, it being possible for each ofthose rings optionally to be substituted by one or more identical ordifferent groups selected from:

halogen,

trihalomethyl,

linear or branched (C₁ -C₆)-alkyl optionally substituted by one or morehalogen atoms or hydroxy groups,

linear or branched (C₁ -C₆)-alkoxy,

linear or branched (C₁ -C₆)-aminoalkyl,

cyano,

aryl and linear or branched aryl-(C₁ -C₆)-alkyl, it being possible forthe aryl moiety of the said groups optionally to be substituted by oneor more identical or different groups selected from halogen, hydroxy,linear or branched (C₁ -C₆)-alkyl and linear or branched (C₁-C₆)-alkoxy,

and sulphonyl substituted by a linear or branched (C₁ -C₆)-alkyl groupor an amino group itself optionally substituted by one or two identicalor different linear or branched (C₁ -C₆)-alkyl groups,

it being understood that:

an aryl group denotes a phenyl or naphthyl group, and a heteroaryl groupdenotes an aryl group containing one, two or three identical ordifferent hetero atoms selected from nitrogen, oxygen and sulphur,

their isomers, and also addition salts thereof with a pharmaceuticallyacceptable acid or base,

provided that:

when A, together with the atoms in common with the pyrrole ring, is acyclohexane or a norbornene and R is a hydrogen atom, R₁ and R₂ cannotsimultaneously each represent a phenyl group,

when R₁ represents a phenyl group, R represents a hydrogen atom

and when R₂ represents a para-nitrophenyl group, then A, together withthe atoms in common with the pyrrole ring, cannot represent anorbornane,

or when R₂ represents a 1-isoquinolyl group, then A, together with theatoms in common with the pyrrole ring, cannot represent a cyclohexane ora 1,2-indanyl group,

and provided also that:

if R₂ represents a 4-pyridyl or 4-quinolyl group, each of those groupsoptionally being substituted by one or more groups selected fromhalogen, linear or branched (C₁ -C₆)-alkyl (itself optionallysubstituted by a hydroxy or linear or branched (C₁ -C₆)-alkoxy group),hydroxy, nitro, amino, linear or branched (C₁ -C₆)-acyl and linear orbranched (C₁ -C₆)-alkoxycarbonyl,

and R₁ represents a phenyl, naphthyl, pyridyl or quinolyl group, each ofthose groups optionally being substituted by one or two groups selectedfrom halogen, linear or branched (C₁ -C₄)-alkyl (itself optionallysubstituted by a halogen atom), linear or branched (C₁ -C₄)-alkoxy,nitro, hydroxy, amino (optionally substituted by one or two linear orbranched (C₁ -C₆)-alkyl groups), linear or branched (C₁-C₄)-alkoxycarbonyl and linear or branched (C₁ -C₄)-alkylthio,

then A, together with the atoms in common with the pyrrole ring, cannotrepresent a saturated monocyclic (C₅ -C₈)-cycloalkyl group or asaturated heterocycle having from 5 to 7 ring members and containing 1or 2 nitrogen atoms, each of such groups optionally being substituted byone or two groups selected from linear or branched (C₁ -C₆)-alkyl,linear or branched (C₁ -C₄)-alkoxy, and aryl.

Advantageously, the preferred compounds of the invention are those offormula (I) wherein:

R₁ and R₂, which may be identical or different, each representsindependently of the other an aryl group optionally substituted by oneor more of any of the groups as defined hereinabove, advantageously byone or more halogen atoms,

and A represents, together with the atoms in common with the pyrrolering, a monocyclic or bicyclic (C₃ -C₁₂)- or advantageously (C₅-C₈)-cycloalkyl group that is saturated or unsaturated but not ofaromatic character, optionally substituted by one or more of any of thesubstituents as defined hereinabove,

their isomers, and also addition salts thereof with a pharmaceuticallyacceptable acid or base.

Especially advantageously, the preferred compounds of the invention arethose of formula (I) wherein A represents, together with the atoms incommon with the pyrrole ring, a bicyclic (C₅ -C₁₂)- or advantageously(C₅ -C₈)-cycloalkyl group that is saturated or unsaturated but not ofaromatic character, optionally substituted by one or more of any of thegroups as defined hereinabove,

their isomers, and also addition salts thereof with a pharmaceuticallyacceptable acid or base.

According to another advantageous variant of the invention, thepreferred compounds are those of formula (I) wherein:

R₁ and R₂, which are identical, each represents a heteroaryl groupoptionally substituted by one or more of any of the groups as definedhereinabove,

and A represents, together with the atoms in common with the pyrrolering, a bicyclic (C₅ -C₂)- or advantageously (C₅ -C₈)-cycloalkyl groupthat is saturated or unsaturated but not of aromatic character,optionally substituted by one or more of any of the groups as definedhereinabove,

their isomers, and also addition salts thereof with a pharmaceuticallyacceptable acid or base.

Finally, very advantageously the preferred compounds of the inventionare the following compounds of formula (I):

1,3-di-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole,

1,3-diphenyl-5,6-dimethyl-4,5,6,7-tetrahydro-2H-isoindole,

1,3-diphenyl-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole,

1,3-di-(4-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrole,

1,3-diphenyl-4,5,6,7-tetrahydro-4,7-ethano-2H-isoindole,

and 1,3-di-(4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole,

their isomers, and also addition salts thereof with a pharmaceuticallyacceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned,without implying any limitation, hydrochloric, hydrobromic, sulphuric,phosphonic, acetic, trifluoroacetic, lactic, pyruvic, succinic,glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic,methanesulphonic, camphoric acid, etc . . . .

Among the pharmaceutically acceptable bases there may be mentioned,without implying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, diethylamine, tert-butylamine, arginine, lysine, etc . .. .

The invention extends also to a process for the preparation of thecompounds of formula (I) which is characterised in that there are usedas starting material:

either compounds of formula (II/a): ##STR3## wherein: A is as definedfor formula (I),

R₃ represents a cyano group and

R₄ represents a linear or branched (C₁ -C₆)alkoxycarbonyl group,

which compounds of formula (II/a) are subjected to the action of amagnesium compound of formula (III):

    R.sub.1 Mg Y                                               (III)

wherein:

R₁ is as defined for formula (I),

and Y represents a halogen atom, such as bromine or chlorine,

to yield the compounds of formula (I/a), a particular case of thecompounds of formula (I): ##STR4## wherein R₁ and A are as defined forformula (I), or compounds of formula (II/b): ##STR5## wherein A, R₁ andR₂ are as defined for formula (I), which are condensed:

either in the presence of an organic acid, such as acetic acid, with acompound of formula (IV):

    R-NH.sub.2                                                 (IV)

wherein R is as defined for formula (I), with the proviso that R isother than a hydrogen atom, to yield the compounds of formula (I/b), aparticular case of the compounds of formula (I): ##STR6## wherein R₁ andR₂, which may be identical or different, are as defined for formula (I),

A is as defined for formula (I) and R is as defined for formula (I) withthe proviso that it is not a hydrogen atom,

which compounds of formula (I/b) are optionally subjected to the actionof a dealkylation, deamination or deacylation agent according to thenature of the group R to yield the compounds of formula (I/c), aparticular case of the compounds of formula (I): ##STR7## wherein R₁, R₂and A are as defined hereinabove, or with ammonium formate HCO₂ ⁻ NH₄ ⁺to yield the compounds of formula (I/c) directly, a particular case ofthe compounds of formula (I): ##STR8## wherein R₁ and R₂ (identical ordifferent), and A are as defined for formula (I),

it being possible for each of the compounds (I/a), (I/b) and (I/c)optionally to be subjected to a catalytic reduction, in the cases wherethe ring A comprises at least one unsaturation, to yield the compoundsof formula (I/d), a particular case of the compounds of formula (I):##STR9## wherein R, R₁ and R₂ are as defined for formula (I) and A'represents an (optionally substituted) saturated, mono- or bi-cyclic (C₃-C₁₂)-cycloalkyl group,

which compounds of formulae (I/a) to (I/d) are purified, if necessary,according to a conventional purification technique, are separated, whereappropriate, into their isomers according to a conventional separationtechnique, and are converted, if desired, into their addition salts witha pharmaceutically acceptable acid or base.

The compounds of formulae (II), ((II/a) and (II/b)), are eithercommercially available compounds or are obtained, in the case of thecompounds of formula (II/a), according to the conditions described by J.Am. Chem. Soc., 1962, 84, 2196 and, in the case of the compounds offormula (II/b), by a Diels-Alder reaction between an unsaturateddiketone and a diene.

The invention extends also to pharmaceutical compositions comprising asactive ingredient at least one compound of formula (I), alone or incombination with one or more pharmacologically acceptable, inert,non-toxic excipients. Of the pharmaceutical compositions according tothe invention there may be mentioned more especially those which aresuitable for oral, parenteral (intravenous, intramuscular orsubcutaneous), percutaneous, transcutaneous, nasal, rectal, perlingual,ocular or respiratory administration, and especially tablets, dragees,sublingual tablets, soft gelatin capsules, hard gelatin capsules,suppositories, creams, ointments, dermal gels, injectable or drinkablepreparations, eye or nose drops etc . . . .

The invention also includes, for their use as medicaments, the followingcompounds, which are particular cases of the compounds of formula (I),wherein:

when R₁ and R₂ are identical and each represents a phenyl group and Rrepresents a hydrogen atom, then A, together with the atoms in commonwith the pyrrole ring, represents a cyclohexane,

and when R₁ and R₂ are identical and each represents a phenyl group andR represents a hydrogen atom, then A, together with the atoms in commonwith the pyrrole ring, represents a norbornene,

and when R₁ represents a phenyl group, R₂ represents a 1-isoquinolylgroup and R represents a hydrogen atom, then A, together with the atomsin common with the pyrrole ring, represents a cyclohexane,

and when R₁ represents a phenyl group R₂ represents a para-nitrophenylgroup and R represents a hydrogen atom, then A, together with the atomsin common with the pyrrole ring, represents a norbornane.

The invention extends similarly to pharmaceutical compositionscomprising as active ingredient at least one compound corresponding toone of those four structures, which are particular cases of thecompounds of formula (I) as defined hereinabove, alone or in combinationwith one or more pharmacologically acceptable, inert, non-toxicexcipients, for use as inhibitors of cyclooxygenase-2, interleukin 1βand inducible nitric oxyde synthase.

The dosage used is adaptable according to the nature and severity of thedisorder, the use of any associated treatments, the administration routeand the age and weight of the patient. That dosage ranges from 0.1 mg to1 g in one or more administrations per day.

The following Examples illustrate the invention but do not limit it inany way.

The starting materials used are known products or are products preparedaccording to known procedures. The different Steps result in synthesisintermediates for use in the preparation of the compounds of theinvention.

The structures of the compounds described in the Examples weredetermined according to conventional spectrophotometric techniques(infra-red, nuclear magnetic resonance, mass spectrometry . . . ).

Preparation:

The products of the various preparations, for use as starting materialsin the synthesis of the compounds of the invention described in thevarious Examples, were obtained by reaction between a diene and adienophile according to the operating conditions described, for example,in J. Am. (hem. Soc., 1940, 62, 56-61.

Preparation 1: 1,2-dimethyl-4,5-dibenzoylcyclohexene

The product is obtained by reaction between the diene,2,3-dimethyl-1,3-butadiene, and a dienophile,1,4-diphenyl-2-butene-1,4-dione.

Preparation 2: 4,5-dibenzoylcyclohexene

The product is obtained by reaction between the diene, 1,3-butadiene andthe dienophile of Preparation 1.

Preparation 3: 5,6-dibenzoylbicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between the diene, cyclopentadieneand the dienophile of Preparation 1.

Preparation 4: 5,6-dibenzoylbicyclo[2.2.2]oct-2-ene

The product is obtained by reaction between the diene,1,3-cyclohexadiene and the dienophile of Preparation 1.

Preparation 5: 5,6-(4-fluorobenzoyl)-bicyclol[2.2.1]hept-2-ene

The product is obtained by reaction between the diene of Preparation 3and a dienophile, 1,4-di-(4-fluorophenyl)-2-butene-1,4-dione.

Preparation 6: 4,5-di-(4-methoxybenzoyl)-cyclohexene

The product is obtained by reaction between 1,3-butadiene and1,4-di-(4-methoxyphenyl)-2-butene-1,4-dione.

Preparation 7: 4,5-di-(4-chlorobenzoyl)-cyclohexene

The product is obtained by reaction between the diene of Preparation 6and 1,4-di-(4-chlorophenyl)-2-butene-1,4-dione.

Preparation 8:2-(4-fluorobenzoyl)-3-[(4-methylsulphonyl)benzoyl]-bicyclo[2.2.1]-heptane

The product of Preparation 5 is treated under the conditions of Example9, then placed in the presence of sodium thiomethanolate in dimethylsulphoxide according to conventional operating conditions. The productobtained is then subjected to oxydation to allow isolation of theexpected product.

Preparation 9: 2,3-di-[(4-methylsulphonyl)benzoyl]-bicyclo[2.2.1]heptane

The product is obtained as co-product in the synthesis of the compoundof Preparation 8.

Preparation 10: 4,5-di-[4-(1H-imidazolyl)benzoyl]cyclohexene

The product is obtained by reaction between the diene of Preparation 6and 1,4-di-(4-fluorophenyl)-2-butene-1,4-dione, followed by treatmentwith imidazole in the presence of potassium hydroxide, in dimethylsulphoxide.

Preparation 11: 5,6-di-(4-pyridylcarbonyl)-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-(4-pyridyl)-2-butene-1,4-dione.

Preparation 12: 5,6-di-(2,4-difluorobenzoyl)-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-(2,4-difluoro-phenyl)-2-butene-1,4-dione.

Preparation 13: 5,6-di-(3,4-difluorobenzoyl)-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-(3,4-difluorophenyl)-2-butene-1,4-dione.

Preparation 14:5,6-di-[(5-fluoro)-2-pyridylcarbonyl]-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-[(5-fluoro)-2-pyridyl]-2-butene-1,4-dione.

Preparation 15:5,6-di-[(6-fluoro)-3-pyridylcarbonyl]-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-[(6-fluoro)-3-pyridyl]-2-butene-1,4-dione.

Preparation 16: 5,6-di-(2-furylcarbonyl)-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-(2-furyl)-2-butene-1,4-dione.

Preparation 17: 5,6-di-(2-thienylcarbonyl)-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-(2-thienyl)-2-butene-1,4-dione.

Preparation 18:5,6-di-[(4-fluoro)-2-nitrobenzoyl]-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-[(4-fluoro)-2-nitrophenyl]-2-butene-1,4-dione.

Preparation 19:5,6-di-[(4-fluoro)-3-nitrobenzoyl]-bicyclo[2.2.1]-hept-2-ene

The product is obtained by reaction between cyclopentadiene and1,4-di-[(4-fluoro)-3-nitrophenyl]-2-butene-1,4-dione.

Preparation 20: 5,6-di-(4-fluorobenzoyl)-bicyclo[2.2.2]oct-2-ene

The product is obtained by reaction between 1,3-cyclohexadiene and thedienophile used in Preparation 5.

Preparation 21:5,6-di-[(4-fluoro)benzoyl]-oxo-7-bicyclo[2.2.1]hept-2-ene

The product is obtained by reaction between a diene, furan and thedienophile used in Preparation 5.

EXAMPLE 1

1,3-di-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole

Step A: tert-butyl cis-2-cyanocyclohexanecarboxylate

46.25 g of cis-cyclohexane-1,2-dicarboxylic anhydride are slowly added,at a temperature below 25° C., to a solution of 66 ml of ION ammoniac.After 18 hours the solution is acidified by the addition of 12Nhydrochloric acid, causing the formation of a precipitate which isfiltered off, washed with water and dried. The 51 g ofcis-2-carboxamido-cyclohexanecarboxylic acid so obtained are mixed with180 ml of pyridine and 75 ml of tert-butanol. 115 ml of benzenesulphonylchloride are then added dropwise while maintaining the temperature atapproximately 40° C. After reaction for 12 hours at ambient temperaturethe solution is hydrolysed by the addition of 600 ml of water and thenextracted with ethyl ether. After washing, the organic phases are driedover calcium sulphate and concentrated. The residue is distilled and55.7 g of the expected product are obtained.

Step B: 1,3-di-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole

A solution of 14.75 g of the compound of Step A diluted with 30 ml ofethyl ether is added dropwise, at 35° C., to 80 ml of a 2M solution of4-fluorophenylmagnesium bromide in ethyl ether. After 2 hours, thereaction mixture is cooled and hydrolysed with 20 ml of a saturatedammonium chloride solution. After filtration and washing with ethylether, the organic phases are combined and dried over calcium sulphateand then concentrated. The product is isolated by chromatography onsilica gel (eluant: cyclohexane/ethyl acetate:97.5/2.5). Crystallisationyields 2 g of the product.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             77.66        5.54   4.53                                             % found 77.26 5.52 4.42                                                     ______________________________________                                    

EXAMPLE 2

1,3-diphenyl-4,5,6,7-tetrahydro-2H-isoindole

The expected product is obtained in accordance with the processdescribed in Example 1, using phenylmagnesium bromide as the reagent inStep B.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             87.87        7.00   5.12                                             % found 87.87 7.28 5.37                                                     ______________________________________                                    

Melting point: 146° C.

EXAMPLE 3

1,3-di(4-methylthiophenyl)-4,5,6,7-tetrahydro-2H-isoindole

The expected product is obtained in accordance with the processdescribed in Example 1, using 4-methylthiophenylmagnesium bromide as thereagent in Step B.

    ______________________________________                                        Elemental microanalysis:                                                                  C      H          N    S                                          ______________________________________                                        % calculated                                                                              72.28  6.34       3.83 17.54                                        % found 72.11 6.40 4.07 17.40                                               ______________________________________                                    

Melting point: 174° C.

EXAMPLE 4

1,3-diphenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole

Step A: tert-butyl cis-2-cyanocyclopentanecarboxylate

The procedure is as in Step A of Example 1, usingcis-cyclopentane-1,2-dicarboxylic anhydride as substrate.

Step B: 1,3-diphenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole

The expected product is obtained by reacting the compound of Step A withthe reagent used in Example 2 in accordance with the conditions of StepB of Example 1.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             87.99        6.61   5.40                                             % found 88.12 6.70 5.38                                                     ______________________________________                                    

Melting point: 190° C.

EXAMPLE 5

1,3-diphenyl-4,7-dihydro-2H-isoindole

Step A: tert-butyl cis-2-cyano-4,5-cyclohexenecarboxylate

The procedure is as in Step A of Example 1, usingcis-4,5-cyclohexene-1,2-dicarboxylic anhydride as substrate.

Step B: 1,3-diphenyl-4,7-dihydro-2H-isoindole

The expected product is obtained by reacting the compound of Step A withthe reagent used in Example 2 in accordance with the conditions of StepB of Example 1.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             88.44        6.18   5.15                                             % found 88.52 6.31 5.16                                                     ______________________________________                                    

Melting point: 138° C.

EXAMPLE 6

1,3-diphenyl-5,6-dimethyl-4,7-dihydro-2H-isoindole

A solution containing 4.46 g of 1,2-dimethyl-4,5-dibenzoylcyclohexene(Preparation 1) and 8.81 g of ammonium formate in 70 ml of anhydrousethanol is heated at reflux for 24 hours. A precipitate is obtainedwhich is filtered off and then dissolved in dichloromethane. The organicphase is washed with water, dried over calcium sulphate and concentratedto allow the isolation of 4 g of the expected product.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             88.25        7.07   4.60                                             % found 87.81 7.04 4.45                                                     ______________________________________                                    

Melting point: 212° C.

EXAMPLE 7

1,3-diphenyl-2,5,6-trimethyl-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as the reagent 10 equivalents ofan aqueous 40% methylamine solution in the presence of 5 equivalents ofacetic acid.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             88.14        7.40   4.47                                             % found 88.30 7.40 4.54                                                     ______________________________________                                    

Melting point: 200-201° C.

EXAMPLE 8

1,3-diphenyl-2-benzyloxycarbonylamino-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as the reagents 5 equivalents ofbenzyloxy-carbonylhydrazine and 5 equivalents of acetic acid.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             79.98        5.75   6.66                                             % found 79.62 5.86 6.56                                                     ______________________________________                                    

Melting point: 184° C.

EXAMPLE 9

1,3-diphenyl-5,6-dimethyl-4,5,6,7-tetrahydro-2H-isoindole

1 g of the product obtained in Example 6, 1.2 g of ammonium formate and0.2 g of 10% Pd/C in 70 ml of ethanol are heated at reflux for 3 hours,then filtered and concentrated. The expected product is isolated bychromatography on silica gel (eluant: cyclohexane/ethyl acetate: 90/10).

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             87.66        7.69   4.65                                             % found 87.44 7.57 4.45                                                     ______________________________________                                    

Melting point: 133° C.

EXAMPLE 10

1,3-diphenyl-2-methyl-4,5,6,7-tetrahydro-2H-isoindole

Step A: 1,3-diphenyl-2-methyl-4,7-dihydro-2H-isoindole

The procedure is as in Example 7, using as substrate4,5-dibenzoylcyclohexene (Preparation 2).

Step B: 1,3-diphenyl-2-methyl-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 9, using as substrate the product of StepA.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             87.76        7.36   4.87                                             % found 87.96 7.22 4.88                                                     ______________________________________                                    

Melting point: 143° C.

EXAMPLE 11

1,3-diphenyl-4,5,6,7-tetrahydro-2H-2-isoindolamine

The procedure is as in Example 9, using as substrate the product ofExample 8.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             83.30        6.99   9.71                                             % found 83.34 7.01 9.58                                                     ______________________________________                                    

Melting point: 161° C.

EXAMPLE 12

1-phenyl-3-(4-methylthiophenyl)-4,5,6,7-tetrahydro-2H-isoindole

Step A: 1-phenyl-3-(4-methylthiophenyl)-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as starting material4-benzoyl-5-(4-methylthio)-benzoylcyclohexene.

Step B: 1-phenyl-3-(4-methylthiophenyl)-4,5,6,7-etrahydro-2H-isoindole

The procedure is as in Example 9, using the product obtained in Step A.

    ______________________________________                                        Elemental microanalysis:                                                                  C      H          N    S                                          ______________________________________                                        % calculated                                                                              78.95  6.63       4.38 10.04                                        % found 78.91 6.61 4.39  9.96                                               ______________________________________                                    

Melting point: 150° C.

EXAMPLE 13

1,3-diphenyl-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

Step A: 1,3-diphenyl-4,7-dihydro-4,7-methano-2H-isoindole

The procedure is as in Example 6, using as substrate the product ofPreparation 3.

Step B: 1,3-diphenyl-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 9, using the product of Step A.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             88.38        6.71   4.91                                             % found 88.44 6.96 4.73                                                     ______________________________________                                    

Melting point: 162° C.

EXAMPLE 14

1,3-diphenyl-2-dimethanesulphonylamino-4,5,6,7-tetrahydro-2H-isoindole

1,3-Diphenyl-4,5,6,7-tetrahydro-2H-2-isoindolamine (Example 11) istreated with 2 equivalents of methanesulphonyl chloride.

    ______________________________________                                        Elemental microanalysis:                                                                  C      H          N    S                                          ______________________________________                                        % calculated                                                                              59.44  5.44       6.30 14.42                                        % found 59.83 5.77 6.31 14.13                                               ______________________________________                                    

Melting point: >250° C. (decomposition).

EXAMPLE 15

1,3-di-(4-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrole

The expected product is obtained by reacting tert-butylcis-2-cyanocyclopentanecarboxylate (Example 4, Step A) in accordancewith the conditions of Step B of Example 1.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             77.27        5.12   4.74                                             % found 77.55 4.87 4.71                                                     ______________________________________                                    

Melting point: 170° C.

EXAMPLE 16

1,3-di(4-methylphenyl)-4,5,6,7-tetrahydro-2H-isoindole

The expected product is obtained in accordance with the processdescribed in Example 1, using 4-methylphenylmagnesium bromide as thereagent in Step B.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             87.66        7.69   4.65                                             % found 87.78 8.02 4.76                                                     ______________________________________                                    

Melting point: 150° C.

EXAMPLE 17

1,3-diphenyl-4,7-dihydro-4,7-ethano-2H-isoindole

The expected product is obtained by reacting the compound of Preparation4 in accordance with the conditions of Example 6.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             88.85        6.44   4.71                                             % found 88.36 6.50 4.72                                                     ______________________________________                                    

Melting point: 224° C.

EXAMPLE 18

1,3-diphenyl-4,5,6,7-tetrahydro-4,7-ethano-2H-isoindole

The expected product is obtained by reacting the compound of Example 17in accordance with the conditions of Example 9.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             88.25        7.07   4.68                                             % found 88.10 7.29 4.62                                                     ______________________________________                                    

Melting point: 248° C.

EXAMPLE 19

1,3-di-(4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

Step A: 1,3-di-(4-fluorophenyl)-4,7-dihydro-4,7-methano-2H-isoindole

The procedure is in accordance with Example 6, using as substrate theproduct of Preparation 5.

Step B:1,3-di-(4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The product obtained in Step A is treated under the conditions ofExample 9, replacing the ammonium formate with cyclohexene.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             78.49        5.33   4.36                                             % found 78.59 5.36 4.40                                                     ______________________________________                                    

Melting point: 146° C.

EXAMPLE 20

1,3-di-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole

Step A: 1,3-di-(4-methoxyphenyl)-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as substrate4,5-di-(4-methoxybenzoyl)cyclohexene (Preparation 6).

Step B: 1,3-di-(4-methoxyphenyl)-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 9, using the product of Step A.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             79.25        6.95   4.20                                             % found 78.65 6.83 4.28                                                     ______________________________________                                    

Melting point: 146° C.

EXAMPLE 21

1,3-di-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole

Step A: 1,3-di-(4-chlorophenyl)-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as substrate4,5-di-(4-chlorobenzoyl)cyclohexene (Preparation 7).

Step B: 1,3-di-(4-chlorophenyl)-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, using the product of Step A.

    ______________________________________                                        Elemental microanalysis:                                                                   C      H          N    Cl                                        ______________________________________                                        % calculated 70.19  5.01       4.09 20.72                                       % found 70.03 5.07 4.20 20.22                                               ______________________________________                                    

Melting point: 231° C.

EXAMPLE 22

1,3-diphenyl-2-carboxymethyl-4,5,6,7-tetrahydro-2H-isoindole

Step A:1,3-diphenyl-2-tert-butoxycarbonylmethyl-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as substrate4,5-dibenzoylcyclohexene (Preparation 2) and as the reagent tert-butyl2-aminoacetate in the presence of acetic acid.

Step B: 1,3-diphenyl-2-carboxymethyl-4,7-dihydro-2H-isoindole

5 ml of trifluoroacetic acid are added at 0° C. to a solution of 5 g ofthe compound of Step A in 50 ml of anhydrous dichloromethane. Afterreaction for 12 hours at ambient temperature, the reaction mixture isconcentrated in vacuo and the residue obtained is rinsed with ether toallow isolation of the expected product.

Step C: 1,3-diphenyl-2-carboxymethyl-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 9, using the product of Step B.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             79.73        6.39   4.23                                             % found 79.72 6.58 4.19                                                     ______________________________________                                    

Melting point: 162° C.

EXAMPLE 23

(d,l)-1-(4-fluorophenyl)-3-[(4-methylsulphonyl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 6, using as substrate the product ofPreparation 8.

    ______________________________________                                        Elemental microanalysis:                                                                   C      H          N    S                                         ______________________________________                                        % calculated 69.27  5.28       3.67 8.41                                        % found 69.16 5.59 3.56 7.94                                                ______________________________________                                    

Melting point: >260° C.

EXAMPLE 24

2-benzyl-4,6-diphenyl-1,2,3,5-tetrahydropyrrolo[3,4-c]pyrrole

The procedure is as in Example 6, using as substrate3,4-dibenzoyl-1-benzyl-2,3,4,5-tetrahydro-1H-pyrrole;

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             85.68        6.33   7.99                                             % found 85.53 6.46 7.97                                                     ______________________________________                                    

Melting point: 182° C.

EXAMPLE 25

1,3-di[(4-methylsulphonyl)phenyl]-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 6, using as substrate the product ofPreparation 9.

    ______________________________________                                        Elemental microanalysis:                                                                   C      H          N    S                                         ______________________________________                                        % calculated 62.56  5.25       3.17 14.52                                       % found 61.93 5.64 3.17 14.14                                               ______________________________________                                    

Melting point: >260° C.

EXAMPLE 26:

1,3-di-[4-(1H-imidazolyl)phenyl]-4,5,6,7-tetrahydro-2H-isoindoledihydrochloride

Step A: 1,3-di-[4-(1H-imidazolyl)phenyl]-4,7-dihydro-2H-isoindole

The procedure is as in Example 6, using as substrate the product ofPreparation 10.

Step B:1,3-di-[4-(1H-imidazolyl)phetiyl]-4,5,6,7-tetrahydro-2H-isoindoledihydrochloride

The procedure is as in Example 9, using the product of Step A.

    ______________________________________                                        Elemental microanalysis:                                                                   C      H          N    Cl                                        ______________________________________                                        % calculated 65.27  5.27       14.64                                                                              14.82                                       % found 65.38 5.59 14.71 15.30                                              ______________________________________                                    

Melting point: >260° C.

EXAMPLE 27

1,3-diphenyl-2H-pyrrolidine[3,4-c]pyrrole hydrochloride

The procedure is as in Example 9, using as substrate the productobtained in Example 24.

Melting point: >260° C.

EXAMPLE 28

1-(4-fluorophenyl)-3-[4-(1H-imidazolyl)phenyl]-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 6, using as substrate2-(4-fluorobenzoyl)-1-[4-(1H-imidazolyl)benzoyl]cyclohexane.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             77.29        5.64   11.76                                            % found 76.76 5.72 11.72                                                    ______________________________________                                    

Melting point: >250° C.

EXAMPLE 29

1,3-di-(4-fluorophenyl)-4,7-dihydro-4,7-methano-2H-isoindole

The procedure is as in Example 19, stopping after Step A.

    ______________________________________                                        Elemental microanalysis:                                                                 C            H      N                                              ______________________________________                                        % calculated                                                                             78.98        4.73   4.39                                             % found 79.30 4.76 4.42                                                     ______________________________________                                    

Melting point: 189° C.

EXAMPLE 30

1,3-diphenyl-2-methanesulphonylamino-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 14, using the same substrate but only oneequivalent of methanesulphonyl chloride as reagent.

    ______________________________________                                        Elemental microanalysis:                                                                   C      H          N    S                                         ______________________________________                                        % calculated 68.83  6.05       7.64 8.75                                        % found 68.94 6.32 7.63 9.07                                                ______________________________________                                    

Melting point: 196° C.

EXAMPLE 31

1,3-di-(4-pyridyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindoledihydrochloride

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 11.

    ______________________________________                                        Elemental microanalysis:                                                                   C      H          N    Cl                                        ______________________________________                                        % calculated 63.34  5.32       11.66                                                                              19.68                                       % found 63.69 5.67 11.73 19.44                                              ______________________________________                                    

Melting point: 264° C.

EXAMPLE 32

1,3-di-(2,4-difluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 12.

EXAMPLE 33

1,3-di-(3,4-difluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 13.

EXAMPLE 34

1,3-di-(5-fluoro-2-pyridyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 14.

EXAMPLE 35

1,3-di-(6-fluoro-3-pyridyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 15.

EXAMPLE 36

1,3-di-(2-furyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 16.

EXAMPLE 37

1,3-di-(2-thienyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 17.

EXAMPLE 38

1,3-di-(2-amino-4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

Step A:1,3-di-(4-fluoro-2-nitrophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindol

The procedure is as in Example 19 Steps A and B, using as substrate inStep A the product of Preparation 18.

Step B:1,3-di-(2-amino-4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

A solution containing 1 equivalent of the compound obtained in Step A in30 ml of methanol and 100 mg of 10% palladium on carbon is heated for 2hours at 40° C. After returning to ambient temperature, the reactionmixture is filtered over Celite and then concentrated under reducedpressure to allow isolation of the expected product.

EXAMPLE 39

1,3-di-(4-fluoro-2-(N-methyl)aminophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

A solution containing 1 equivalent of the compound obtained in Example38 is reacted at ambient temperature in formaldehyde in the presence offormic acid in accordance with the conditions described in Org. React.,1949, 5, 290 to allow isolation of the expected product.

EXAMPLE 40

1,3-di-(4-fluoro-2-dimethylaminophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

A solution containing 1 equivalent of the compound obtained in Example38, 2.2 equivalents of methyl iodide and 2 equivalents of K₂ CO₃ in 40ml of dimethylformamide is stirred for 12 hours at ambient temperature.After concentration at reduced pressure the residue is diluted withdichloromethane and then the organic phase is washed with a saturatedNaCl solution. After drying over sodium sulphate and concentration underreduced pressure, chromatography on silica gel allows isolation of theexpected product.

EXAMPLE 41

1,3-di-(3-amino-4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 38, Steps A and B, using as substrate inStep A the product obtained in Preparation 19.

EXAMPLE 42

1,3-di-(4-fluoro-3-(N-methyl)aminophenyl)-4,7-methano-4,5,6,7-2H-isoindole

The procedure is as in Example 39, using as substrate the productobtained in Example 41.

Melting point: 196° C.

EXAMPLE 43

1,3-di-(4-fluoro-3-dimethylaminophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The procedure is as in Example 40, using as substrate the productobtained in Example 41.

EXAMPLE 44

1,3-di-(4-fluorophenyl)-4,5,6,7-tetrahydro-4,7-ethano-2H-isoindole

The expected product is obtained by reacting the compound of Preparation20 in accordance with the conditions of Example 6, then in accordancewith the conditions of Example 9.

EXAMPLE 45

1,3-di-(3-acetamido-4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole

The expected product is obtained by reacting the compound of Example 41under conventional acylation conditions.

Melting point: 225° C.

EXAMPLE 46

5,7-di-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,4-epoxy-6H-isoindole##STR10##

The procedure is as in Example 19, Steps A and B, using as substrate inStep A the product of Preparation 21.

PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE 47

Biological activity of the compounds on cyclooxygenase 1 and 2

The inhibitory activities of the compounds in relation to COX 1 and COX2 were evaluated using mice peritoneal macrophages exposed toinflammatory stimuli (zymosan and LPS, respectively) in accordance withthe method described by Tordjman el al., Biochimica et Biophysica Acta,1995, 1256, 249-56.

The results are given in Table 1:

                  TABLE 1                                                         ______________________________________                                                    IC.sub.50 (μM)                                                 Example       cox 1   cox 2                                                   ______________________________________                                        1             0.1-0.5 0.001                                                     2 0.1-0.5 0.001                                                               4 0.1-0.5 0.0005-0.001                                                        5 0.1 0.001-0.01                                                              19  0.1 0.001                                                               ______________________________________                                    

The compounds also inhibit the production of IL1β by THP1 line cellsstimulated with LPS. For example, the compound of Example 9 has an IC₅₀of the order of 1 μM in that model. In addition, those compounds exertan activity in animals especially by inhibiting the production ofprostaglandins in the carrageenin air-pouch model in the mouse (Whittle,B. J. R. et al., Nature, 1980, 284, 271-273; Masferrer, J. L. el al.,Proc. Natl. Acad. Sci. USA, 1994, 91, 3228-3232). Thus, in that model,the compound of Example 19 exhibits a powerful activity having an oralED₅₀ of 2.5 mg/kg. Gastric tolerance, evaluated in the mouse afterfasting for 24 hours and 5 hours after oral treatment, has provedexcellent for all of the compounds: absence of macroscopic effects up toa dose of 800 mg/kg. In addition, the present compounds inhibited the NOproduction in mouse peritoneal macrophages stimulated with LPS. Forexample, the compound of Example 19 exhibited a concentration-relatedinhibition with an IC₅₀ value of 2,5 μM.

EXAMPLE 48

Formulation for the preparation of 1000 tablets each comprising 10 mg ofactive ingredient

    ______________________________________                                        1,3-di(4-fluorophenyl)-4,7-methano-                                                                10 g                                                       4,5,6,7-tetrahydro-2H-isoindole                                               wheat starch 10 g                                                             lactose 100 g                                                                 magnesium stearate 3 g                                                        silica 2 g                                                                    hydroxypropyl cellulose 2 g                                                 ______________________________________                                    

We claim:
 1. A compound selected from those of formula (I): ##STR11## inwhich R represents:hydrogen, a linear or branched (C₁ -C₆)-alkyloptionally substituted by one or more identical or differents groupsselected from hydroxy, linear or branched (C₁ -C₆)-alkoxy, carboxy, andlinear or branched (C₁ -C₆)-alkoxycarbonyl, an amino optionallysubstituted by one or two identical or different groups selected fromlinear or branched (C₁ -C₆)-alkyl, linear or branched (C₁-C₆)-alkoxycarbonyl, linear or branched aryl-( C₁ -C₆)-alkoxycarbonyl,linear or branched (C₁ -C₆)-alkylsulphonyl, and arylsulphonyl, or alinear or branched (C₁ -C₆)-acyl, R₁ and R₂, which may be identical ordifferent, each represents independently of the other aryl, furyl,thienyl, or (C₃ -C₇)-cycloalkyl, or one of said R₁ and R₂ groups whichis substituted by one or more identical or different groups selectedfrom:halogen, linear or branched (C₁ -C₆)-alkyl optionally substitutedby one or more identical or different groups selected from halogen,hydroxy, linear or branched (C₁ -C₆)-alkoxy, amino and linear orbranched (C₁ -C₆)-alkoxycarbonyl, linear or branched (C₁ -C₆)-alkoxyoptionally substituted by amino which is itself optionally substitutedby one or two identical or different linear or branched (C₁ -C₆)-alkyl,linear or branched (C₁ -C₆)-trihaloalkoxy, linear or branched (C₁-C₆)-acyl, hydroxy, nitro, cyano, mercapto, or carboxy, amino optionallysubstituted by one or two identical or different groups selected fromlinear or branched (C₁ -C₆)-alkyl, linear or branched (C₁-C₆)-alkylcarbonyl, and, linear or branched (C₁ -C₆)-alkylsulphonyl,linear or branched (C₁ -C₆)-alkoxycarbonyl, linear or branched (C₁-C₆)-alkylthio, sulphonyl substituted by linear or branched (C₁-C₆)-alkyl or by amino which is itself optionally substituted by one ortwo identical or different linear or branched (C₁ -C₆)-alkyl, and furylor thienyl or one of said furyl or thienyl groups optionally substitutedby one or more identical or different groups selected from halogen,linear or branched (C₁ -C₆)-alkyl, and, linear or branched (C₁-C₆)-alkoxy, A represents, together with the atoms in common with thepyrrole:saturated or unsaturated monocyclic or bicyclic (C₃-C₁₂)-cycloalkyl (with the proviso that the unsaturation(s) present inthe cycloalkyl does(do) not confer on it an aromatic character), or7-oxabicyclo[2.2.1]heptane, or one of said A group which is substitutedby one or more identical or different groups selected from:halogen,trihalomethyl, linear or branched (C₁ -C₆)-alkyl optionally substitutedby one or more halogen or hydroxy, group(s) linear or branched (C₁-C₆)-alkoxy, linear or branched (C₁ -C₆)-aminoalkyl, cyano, aryl orlinear or branched aryl-( C₁ -C₆)-alkyl, the aryl of the said groupsoptionally substituted by one or more identical or different groupsselected from halogen, hydroxy, linear or branched (C₁ -C₆)-alkyl, andlinear or branched (C₁ -C₆)-alkoxy, and sulphonyl substituted by linearor branched (C₁ -C₆)-alkyl or by amino which is itself optionallysubstituted by one or two identical or different linear or branched (C₁-C₆)-alkyl,their isomers, and also addition salts thereof with apharmaceutically-acceptable acid or base, provided that: when A,together with the atoms in common with the pyrrole ring, is cyclohexaneor norbornene and R is hydrogen, R₁ and R₂ cannot simultaneously eachrepresent phenyl, when R₁ represents phenyl, R represents hydrogenandwhen R₂ represents para-nitrophenyl, then A, together with the atoms incommon with the pyrrole ring, cannot represent norbornane,and providedalso that: when A, together with the atoms in common with the pyrrolering, is cyclopentane substituted by 4-methoxyphenyl-methyl, and R ismethyl, R₁ and R₂ cannot simultaneously each represent phenyl.
 2. Acompound of claim 1 wherein:R₁ and R₂, which may be identical ordifferent, each represents independently of the other aryl optionallysubstituted by one or more substituents as defined in claim 1, and Arepresents, together with the atoms in common with the pyrrole ring, amonocyclic or bicyclic (C₃ -C₁₂)- or preferably (C₅ -C₈)-cycloalkyl thatis saturated or unsaturated but not of aromatic character, optionallysubstituted by one or more substituents as defined in claim 1,theirisomers, and also addition salts thereof with apharmaceutically-acceptable acid or base.
 3. A compound of claim 1wherein: A represents, together with the atoms in common with thepyrrole ring, a bicyclic (C₅ -C₁₂)- or (C₅ -C₈)-cycloalkyl that issaturated or unsaturated but not of aromatic character, optionallysubstituted by one or more groups as defined in claim 1,their isomers,and also addition salts thereof with a pharmaceutically-acceptable acidor base.
 4. A compound of claim 1 wherein:R₁ and R₂, which areidentical, each represents furyl or thienyl optionally substituted byone or more groups as defined in claim 1, and A represents, togetherwith the atoms in common with the pyrrole ring, a bicyclic (C₅ -C₁₂)- or(C₅ -C₈)-cycloalkyl that is saturated or unsaturated but not of aromaticcharacter, optionally substituted by one or more groups as defined inclaim 1,their isomers, and addition salts thereof with apharmaceutically-acceptable acid or base.
 5. A compound of claim 1,which is 1,3-di-(4-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole.
 6. Acompound of formula (I) according to claim 1, which is1,3-diphenyl-5,6-dimethyl-4,5,6,7-tetrahydro-2H-isoindole.
 7. A compoundof claim 1, which is1,3-diphenyl-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole.
 8. A compoundof claim 1, which is1,3-di-(4-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrrole.
 9. Acompound of claim 1, which is1,3-diphenyl-4,5,6,7-tetrahydro-4,7-ethano-2H-isoindole.
 10. A compoundof claim 1, which is1,3-di-(4-fluorophenyl)-4,7-methano-4,5,6,7-tetrahydro-2H-isoindole. 11.A pharmaceutical composition useful as a cyclooxygenase-2 inhibitor,and/or interleukine 1β inhibitor, and/or inducible nitric oxyde synthaseinhibitor, comprising as active principle an effective amount of acompound as claimed in claim 1, in combination with one or morepharmaceutically-acceptable excipients or carriers.
 12. A pharmaceuticalcomposition useful as a cyclooxygenase-2 inhibitor, and/or interleukine1β inhibitor, and/or inducible nitric oxyde synthase inhibitor,comprising as active principle an effective amount of a compound asdefined in claim 1, in combination with one or morepharmaceutically-acceptable excipients or carriers.
 13. A method fortreating a living body afflicted with a condition requiringcyclooxygenase-2 inhibitor, and/or interleukine 1β inhibitor, and/orinducible nitric oxyde synthase inhibitor, comprising the step ofadministering to the living body an amount of a compound of claim 1which is effective for alleviation of said condition.
 14. A method fortreating a living body afflicted with a condition requiringcyclooxygenase-2 inhibitor, and/or interleukine 1β inhibitor and/orinducible nitric oxyde synthase inhibitor, comprising the step ofadministering to the living body an amount of a compound of claim 1wherein:R₁ and R₂, which are identical, each represents a phenyl group,R is a hydrogen atom, and A is a cyclohexane, or R₁ and R₂, which areidentical, each represents a phenyl group, R is a hydrogen atom, and Ais a norbornene, or R₁ represents a phenyl group, R₂ represents a1-isoquinolyl group, R represents a hydrogen atom and A is acyclohexane, or R₁ represents a phenyl group, R₂ represents apara-nitrophenyl group, R represents a hydrogen atom and A is anorbornane,which is effective for alleviation of said condition.